Type 2 Diabetes in Children and Adolescents

Transcription

1 Type 2 Diabetes in Children and Adolescents Ann Marie Straight MD LTC, USA, MC Pediatric Endocrinologist BAMC Ann Marie Straight MD LTC, USA, MC has no relevant financial relationships with commercial interests to disclose. Overview 1) Epidemiology 2) Pathogenesis of T2DM 3) Symptoms at presentation 4) Screening for asymptomatic* 5) Making the Diagnosis T2DM* 6) Lab evaluation 7) Treatment 8) Management of co-morbid conditions 9) Follow-up 10) Hyperglycemic Hyperosmolar Syndrome *Based on recommendations made in the 2011 ADA Clinical Practice Guidelines.

2 Epidemiology Type 2 DM T2DM considered an adult disease until recently Prevalence of T2DM has followed prevalence of obesity. SEARCH for Diabetes in Youth T2DM uncommon<10yo regardless of race/ethnicity Incidence 10-14yo and is highest in 15-19yo T2DM 20% new cases DM 10-19yo Can account for as much as 50% of new cases in AA, AI, API, H youth Pathophysiology of T2DM Normal glycemic control requires: 1)Sensing of the glucose concentration by cells 2)Synthesis and release of insulin 3)Binding of insulin to receptors 4)Increased glucose uptake by muscles, fat, and liver 5)Decreased glucose production by the liver Type 2 DM results from a progressive Insulin secretory defect on the background Of insulin resistance. Pathophysiology of T2DM 1)Insulin resistance 2)ß-cell dysfunction Inherited Acquired from glucotoxicity and lipotoxicity 3)Relative or absolute insulin deficiency

3 Cell dysfunction with Impaired first-phase insulin response and Post-prandial hyperglycemia Insulin Resistance Hyperinsulinemia + Normal glucose tolerance Hyperinsulinemia + Postprandial hyperglycemia cell Exhaustion Type2DM Ins Resistance cell function Hepatic gluc production Risk factors and markers: 1)Minority population 2)Family hx T2DM Genetic predisposition 3)IUGR-2-7fold increased risk T2DM 4)Obesity 5)Puberty-increased growth hormone Glucotoxicity Lipotoxicity Latent Autoimmunity Symptoms of T2DM Insidious onset Symptoms x months to years without realization Symptoms may include: Wt loss Fatigue Blurred vision Polyuria, nocturia, polydipsia, polyphagia Recurrent candidal infections Many report no symptoms at time of diagnosis despite having high bgs CRITICAL TO SCREEN FOR DM Screening for T2DM

4 Testing Asymptomatic Children Age 10 or signs of puberty AND BMI > 85% AND Any 2 of the following are present: 1)High-risk ethnic group (Native American, AA, Latino, Asian American, Pacific Islander) 2)Family hx of DM in first or second degree relatives 3)Signs of insulin resistance/conditions associated with insulin resistance (acanthosis nigricans, dyslipidemia, hypertension, PCOS, SGA) 4)Maternal hx of diabetes or gestational DM Case Presentation: JS HPI:16 yo AA male w/ ADD presents for Concerta refill PMHx: ADD, obesity, hyperlipidemia Family Hx: Strong family hx T2DM, obesity, HTN. Mom had gestational DM and has had T2DM x 7 years-on lantus and metformin. Meds: Concerta ROS: Denies wt loss, polyuria, polydipsia,nocturia, blurred vision Case Presentation: JS PE: BP 123/66, HR 66 Wt 110kg (>>97%) HT 173cm (25-50%) BMI 36.6 (>>97%) Well appearing Well hydrated +Acanthosis nigricans No HSM Asymptomatic but screened because: 1)Age >10 2)BMI>85% AND 3)AA, family hx, hyperlipidemia, acanthosis

5 Screening for DM Recommended studies include one of the following: Fasting plasma glucose (FPG) HgA1c 2 hour OGTT Screening for DM: HgA1c HgA1c (%) Mean Plasma Glucose RBC has a lifespan of 3-4 months RBCs bind irreversibly to glucose The percent of total hemoglobin That has glucose attached to it. Estimated blood sugar control for Past 3-4 months. Normal is 5.6%. Convenient, does not require fasting Not influenced by acute stress or Illness More expensive NHANES data indicate that HgA1c 6.5 % may identify up to 1/3 fewer Cases of DM than fasting bg 126 Screening for DM : OGTT No carbohydrate restriction prior to the study Fasting 8-10 hours Obtain baseline glucose If weight <43kg, give 1.75g/kg Drink mixture-5 minutes Obtain 2 hour value Normal fasting <100 Normal 2hr <140 mg/dl

6 Diagnosing DM Diagnosing DM Fasting plasma glucose (FPG) 126mg/dl 2hr plasma glucose of 200 mg/dl during an oral glucose tolerance test Hemaglobin A1c 6.5% In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing Symptoms of hyperglycemia and random plasma glucose 200mg/dl Diagnosing Prediabetes Impaired fasting glucose (IFG) FPG mg/dl Impaired glucose tolerance (IGT) 2hr PG mg/dl HgA1c % Increased risk for developing DM and cardiovascular disease (CVD) Associated with obesity, dyslipidemia (hightg, low HDL), and HTN

7 Additional Studies at Diagnosis Chem panel Degree of hyperglycemia Acidosis Hypernatremia, hypokalemia +/- Serum osmolality Insulin and c-peptide Usually elevated in T2DM May be LOW due to glucose-toxicity and impaired B cell function Re-test 3-6 months IGFBP1 is suppressed by insulin. T1 and T2 Antibody levels Islet cell, insulin Ab, GAD Ab 20% of children with T2DM will have +GAD Ab Positivity increases the likelihood that insulin therapy will be needed HgA1c Duration of highs Choice of initial therapy Type 1 DM Type 2 DM Family Hx 3-5% % Age Variable >10, pubertal Asymptomatic Rare Common Symptoms Days/Weeks Months BMI at Dx <75% >85% Acanthosis No Common Degree of Hyperglycemia Variable Variable Ketosis/ketonuria Common Mod Common Acidosis Common 25% DKA Insulin/C-peptide Low Low-High Autoimmune Markers + 20% Additional Studies at Diagnosis Lipids: Hyperlipidemia is a common finding in T2DM It is the leading cause of mortality in this population Screen after glycemic control achieved Liver enzymes: 5-10% adults with T2DM have NASH Microalbumin True duration of diabetes at time of diagnosis is unknown Ophthalmology Evaluation

8 Fasting bg = 220 Fasting bg = 242 Dx: DM Type 2: +family hx AA obesity acanthosis Case Presentation: JS Case Presentation: JS BG 220, HCO3 29 Insulin 37.4 (nl ), c-peptide not obtained HgA1c= 9.1 (bg= 210), Antibodies neg UA with >1000 glucose but neg ketones BUN/Creatinine wnl Urine for microalumin/creatinine wnl LFTs: AST = 48 and ALT= 72 Ophthalmology evaluation ordered and wnl Treatment

9 Treatment of Prediabetes Dietary counseling Weight loss Physical activity 150min/week Follow progress Consider metformin if IFG or IGT and: Highest risk of developing DM No progress Rescreen for DM every year Treatment DM:Goals 1) Normalize fasting and post-prandial blood sugars Fasting bg mg/dl Post-prandial <180 mg/dl HgA1c 7% 2) Control associated comorbid conditions 3) Prevent microvascular + macrovascular complications Aggressive reduction of insulin resistance early in T2DM is beneficial for β cell preservation and prolonged glycemic control. Keep treatment plan as clear and simple as possible. Frequent follow-up to ensure compliance. Treatment: Medical Nutritional Therapy Cornerstone of treatment for IFG, IGT, and Type 2 DM. Develop healthy, sustainable eating habits: Monitor carbohydrate and sodium intakes Limit saturated fat to <7% total calories, limit trans fat Increase fiber (age + 5g/day or 20-25g/d) Achieve weight loss (7%) 150 minutes of physical activity per week If DM, begin metformin

10 Treatment: Metformin FDA approved for children First line oral agent Mechanism of action: hepatic gluconeogenesis muscle insulin sensitivity liver insulin sensitivity Good for fasting hyperglycemia May lower HgA1c 1-2% No risk hypoglycemia Wt stabilizing Begin with 500mg at dinner and increase by 500mg a week to 1000mg po bid. Monitor fasting blood sugar qd and 2 hour post-dinner a few days a week. May help restore ovulation in PCOS Treatment: Metformin Most common side effects: GI upset (gas, diarrhea, abd pain, nausea, vomiting) Resolves in 2 weeks of therapy Less likely to occur if initial dose is low 500mg po bid and dose is taken with food Recommended dose is 1000mg po bid Megaloblastic Anemia - Interferes with B12 absorption Treatment: Metformin Lactic Acidosis Rare (1/30,000 patient years)but serious complication of metformin use Need to document that patient counseled Malaise, somnolence, myalgias, respiratory distress, abdominal discomfort Contraindicated in: Renal insufficiency, dehydration, metabolic acidosis, hepatic dysfunction, hemodynamic instability If radiocontrast or surgery, hold for 48 hrs after procedure

11 Treatment: Insulin Therapy -Indicated at diagnosis if: Random glucose is > 250 mg/dl Symptoms of hyperglycemia Ketosis or ketoacidosis HgA1c 10 -Indicated as adjunctive therapy to metformin if: Lifestyle and metformin maximized HgA1c >8 -Associated with: hypoglycemia and weight gain -Type of insulin used depends on patient and practitioner Cell dysfunction with Impaired first-phase insulin response and Post-prandial hyperglycemia Insulin Resistance Hyperinsulinemia + Normal glucose tolerance Hyperinsulinemia + Postprandial hyperglycemia cell Exhaustion Type2DM Ins Resistance cell function Hepatic gluc production Risk factors and markers: 1)Minority population 2)Family hx T2DM Genetic predisposition 3)IUGR-2-7fold increased risk T2DM 4)Obesity 5)Puberty-increased growth hormone Glucotoxicity Lipotoxicity Latent Autoimmunity Treatment: Insulin Therapy -Indicated at diagnosis if: Random glucose is > 250 mg/dl Symptoms of hyperglycemia Ketosis or ketoacidosis HgA1c 10 -Indicated as adjunctive therapy to metformin if: Lifestyle and metformin maximized HgA1c >8 -Associated with: hypoglycemia and weight gain -Type of insulin used depends on patient and practitioner

12 Treatment: Insulin Therapy Lantus 10 units qhs with plan to increase by 2 units q 2 days to goal fasting bg <120 May try U/kg/day Education on: Hypoglycemia symptoms Glucagon use Exercise and DM Need for medical alert Sick day management Will need meal coverage if HgA1c > 8 Treatment: Other Pharmacologic Agents Aims of therapy: 1)Increase insulin sensitivity 2)Increase insulin secretion 3)Slow post-prandial glucose absorption Drug Classes: 1) Sulfonylureas 2)Meglitinides 3) Thiazolindinediones 4) Incretin mimetics 5) Dipeptidly-peptidase-4 inhibitors 6) glucosidase inhibitors Treatment: Sulfonylureas Not FDA approved for adolescents Used as adjunctive therapy to Metformin if HgA1c remains Mechanism of action Increases insulin secretion Taken bid 30 min prior to meals Good for post-prandial hyperglycemia May lower HgA1c 1-2% Side effects include: Hypoglycemia Weight gain Meglitinides also lower glucose by binding to the sulfonylurea receptor.

13 Treatment: Thiazolidinediones (TZDs) Not FDA approved for adolescents Used as adjunctive therapy to metformin Mechanism of action: Activates a nuclear receptor Peroxisome Proliferator Actived Receptor Increased insulin sensitivity Good for fasting hyperglycemia No risk hypoglycemia May lower HgA1c 1-1.5% Side effects include: Edema,wt gain? bone fracture rate May take 6+ weeks to see benefit Incretins:Glucagon-Like Peptide 1 Incretins are gut derived peptides that are normally secreted in response to a meal. GLP-1 is the most widely studied incretin. GLP-1 acts to: 1)Stimulate insulin release from pancreatic β cells in response to glucose 2)Suppress glucagon release from pancreatic α cells 3)Slow gastric emptying 4)Increase satiety GLP-1 is typically degraded quickly by dipeptidyl-peptidase-4

14 Treatment: GLP-1 Agonists Not FDA approved for adolescents Only available as injection given bid before meals Good for controlling post-prandial hyperglycemia Can drop HgA1c by 1% Promote weight loss! Side effects include: Nausea and vomiting? Increased risk of pancreatitis Treatment: DPP-4 Inhibitors Mechanism of action: Inhibit the enzyme which degrades Endogenous incretin hormones. Given po qd, no dose titration May lower HgA1c % Reported urticaria, angioedema? Risk of pancreatitis Expensive Treatment: α-glucosidase Inhibitor Taken with carbohydrate containing meals Decreases carbohydrate absorption and post-prandial glucose Excursions. Minimal decrease in HgA1c 0.5% Side effects: abdominal distention, gas

15 Management of Co-morbid Conditions HTN: Increases risk for renal insufficiency, retinopathy, and neuropathy Lifestyle modifications when BP 90-95% Pharmacological therapy (ace-inhibitor) when BP at or above 95% Hyperlipidemia: Goal is: LDL<100mg/dL, HDL >35mg/dL, TG < 150mg/dL Consider statin therapy if LDL mg/dL Initiate therapy if LDL > 160mg/dL Management of Co-morbid Conditions Depression Sleep apnea PCOS Type 2 DM: Follow-up Close follow-up needed because compliance can be more of an issue than in Type 1. Nutrition therapy Clinic visit q 3 months: Follow wt, BMI, BP Exercise routine and diet Blood sugar log, HgA1c Annual labs to include: LFTs, lipids, TFTs, microalbumin Dilated eye exam annually Influenza vaccine Psychology services Diabetes education: sick day management

16 Hyperglycemic Hyperosmolar Syndrome(HHS) HHS Incidence in pediatric T2DM Obese, AA males Present at diagnosis (4%) or can develop during illness/non-compliance Case fatality rate of 12% Symptoms: Polyuria, polydipsia, nocturia Abd pain, nausea, vomiting HA, lethargy Wt loss HHS DKA Hyperglycemia to ++ Ketosis/Acidosis -/+ +++ Dehyration to +++ Osmolality to +++ Electrolyte Deficits to +++ Diagnostic criteria: Glucose >600mg/dL Serum osm >330mOsm/kg Lack of significant acidosis HCO3>15 Lack of significant ketosis HHS: Pathophysiology Relative insulin deficiency/stress Hyperglycemic hyperosmolar state No lipolysis or ketogenesis Prolonged polyuria leads to severe Dehydration and electrolyte losses ( K, Phos, Mg) Hypertonicity of ECF may mask signs of hypovolemia Acidosis is typically due to poor Perfusion, lactic acidosis Zeitler et al. J Pediatrics 2010; 158(1):9-14.

17 HHS:Treatment Restore intravascular volume Bolus 20cc/kg NS at dx Assume 12-15% fluid down Replace over 24-48hrs with 0.45% to 0.75% NS 20 KCl and 20 KPhos Replace UO q 2hrs Gradual correction of : Osmolality Hyperglycemia ( mg/dL/hr) Hypernatremia ( 0.5mEq/L/hr) Fluid therapy corrects hyperglycemia Dilution Increased renal perfusion Increased tissue perfusion Insulin therapy not critical initially HHS: Treatment Insulin therapy may be dangerous Worsen intravascular volume Worsen hypokalemia Insulin therapy should be considered if glucose no longer dropping with fluids alone.

18 HHS:Treatment Complications: Vascular collapse Hypokalemia and arrhythmia Hypophosphatemia and rhabomyolysis risk thrombosis Malignant hyperthermia-like syndrome Pancreatitis Mental status changes Cerebral edema much less common than in DKA Monitor: Hourly glucose and vital signs Q2hrs CMP, Osmolality, fluid balance,ck Q4hrs Ca, Phos, Mg Continuous cardiac monitor Summary T2DM now accounts for 8-45% of all new pediatric and adolescent cases of diabetes. Most patients are asymptomatic at diagnosis. It is critical to be familiar with ADA screening guidelines. Once diagnosis is made, test for micro and macrovascular complications. Treatment involves: lifestyle modification, nutrition therapy, oral hypoglycemic agents, insulin, management of co-morbidities. Keep treatment plan simple and follow-up frequent. Patient can present in HHS or can develop HHS when ill / non-compliant References Mayer-Davis E. Type 2 diabetes in youth: epidemiology and current research toward prevention and treatment. J of the American Dietetic Association 2008; 108(4): S Morales A, Rosenbloom A. Death caused by hyperglycemic hyperosmolar state at the onset of Type 2 Diabetes. J Pediatrics 2004; 144: Sellers E. Clinical management of type 2 diabetes in indigenous youth. Pediatric Clinics of North America 2009; The Writing Group for SEARCH. Incidence of diabetes in youth in the United States. JAMA 2007; 297(24): Zeitler P, Epstein L, Grey M, et al. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatric Diabetes 2007; 8(2): Zeitler P, Hagg A,Rosenbloom A, et al. Hyperglycemic hyperosmolar syndrome in children: pathophysiologic Considerations and suggested guidelines for treatment. J Pediatrics 2010;158(1):9-14.

19 Antibodies and T2DM -Found in 10-20% of adults with presumed T2DM -Explained by the accelerator hypothesis : Insulin resistance->hyperglycemia ->glucose toxicity -> Beta cell apoptosis with development of cell autoimmunity -Antibodies indicate: Earlier need for insulin therapy (esp GAD) Concern for other autoimmune illnesses (TFTS, celiac)